Abstract 585: Sivelestat Attenuates Angii-induced Abdominal Aortic Aneurysms In Apolipoprotein E-deficient Mice

Hypothesis: We assessed the hypothesis that sivelestat (Siv) has a protective effect against AngII-induced AAA. Methods: Male apolipoprotein E-deficient mice were divided into 3 groups: vehicle+saline (n=8), AngII+saline (n=14), and AngII+Siv (n=17). All mice were infused with saline or AngII (1000 ng/kg/min) for 28 days. They were also administered intraperitoneally with either Siv (100 mg/kg) or vehicle twice daily from the infusion of pumps for 28 days. In vitro study, human aortic smooth muscle cells (HASMCs) were pretreated with Siv (100 μM) or DMSO and stimulated with 0.1 μg/ml human neutrophil elastase for 24h. Results: No significant difference was found in body weight and plasma concentrations of total cholesterol among the 3 groups. AngII infusion significantly increased aortic width compared to the saline group ( p =0.011). Siv administration attenuated dilatation of aortic width ( p =0.022). The incidence of AAAs in AngII-infused mice not administered Siv was 93%. Siv significantly decreased the incidence to 47% ( p =0.009). Pronounced disruptions of medial layers were observed in the AngII+saline group, elastin fragmentation induced by AngII was markedly reduced by Siv. A large number of CD68 positive cells and many Gr-1 positive cells were dominantly observed in the AngII+saline group. In the Siv treatment group, few infiltrations of inflammatory cells were observed. Both pro-form and active-form MMP-2 were increased by AngII and reduced by Siv (pro-form: p =0.07, active-form: p <0.05). Both pro-form and active-form MMP-9 were increased by AngII, and only active-form MMP-9 was reduced by Siv (active-form: p <0.05). In the AngII 4-week infusion study, plasma elastase concentration ( p =0.041) and its activity ( p =0.011) were increased by AngII. These increases were significantly attenuated by Siv (concentration: p =0.010, activity: p =0.027). A significant correlation was observed between aortic width and plasma elastase activity (R=0.6976, p <0.0003). In vitro study, MMP-2 activity was induced by elastase, which was attenuated by Siv treatment in medium ( p <0.01) and protein of HASMCs ( p =0.01). Conclusions: Siv attenuates AngII-induced AAA in mice through inhibition of neutrophil elastase.